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Updated: Jul 4, 2025
Assessment of Ovarian Cancer Spheroid Attachment and Invasion of Mesothelial Cells in Real Time
Published on: May 20, 2014
Involvement of Protease-Activated Receptor2 Pleckstrin Homology Binding Domain in Ovarian Cancer: Expression in
Jeetendra Kumar Nag1, Sorina Grisaru-Granovsky2, Shunit Armon2
1Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
Abstract:
Studying primordial events in cancer is pivotal for identifying predictive molecular indicators and for targeted intervention. While the involvement of G-protein-coupled receptors (GPCRs) in cancer is growing, GPCR-based therapies are yet rare. Here, we demonstrate the overexpression of protease-activated receptor 2 (PAR2), a GPCR member in the fallopian tubes (FTs) of high-risk BRCA carriers as compared to null in healthy tissues of FT. FTs, the origin of ovarian cancer, are known to express genes of serous tubal intraepithelial carcinoma (STICs), a precursor lesion of high-grade serous carcinoma (HGSC). PAR2 expression in FTs may serve as an early prediction sensor for ovarian cancer. We show now that knocking down Par2 inhibits ovarian cancer peritoneal dissemination in vivo, pointing to the central role of PAR2. Previously we identified pleckstrin homology (PH) binding domains within PAR1,2&4 as critical sites for cancer-growth. These motifs associate with PH-signal proteins via launching a discrete signaling network in cancer. Subsequently, we selected a compound from a library of backbone cyclic peptides generated toward the PAR PH binding motif, namely the lead compound, Pc(4-4). Pc(4-4) binds to the PAR PH binding domain and blocks the association of PH-signal proteins, such as Akt or Etk/Bmx with PAR2. It attenuates PAR2 oncogenic activity. The potent inhibitory function of Pc(4-4) is demonstrated via inhibition of ovarian cancer peritoneal spread in mice. While the detection of PAR2 may serve as a predictor for ovarian cancer, the novel Pc(4-4) compound may serve as a powerful medicament in STICs and ovarian cancer. This is the first demonstration of the involvement of PAR PH binding motif signaling in ovarian cancer and Pc(4-4) as a potential therapy treatment.
Insights
Protease-activated receptor 2 (PAR2) is overexpressed in fallopian tubes of BRCA carriers, indicating potential for early ovarian cancer prediction. A novel compound, Pc(4-4), inhibits PAR2
Area of Science:
- Oncology
- Molecular Biology
- G-protein-coupled receptor signaling
Background:
- G-protein-coupled receptors (GPCRs) are increasingly implicated in cancer, yet GPCR-targeted therapies remain limited.
- Protease-activated receptor 2 (PAR2) is a GPCR member.
- Fallopian tubes (FTs) are the origin of high-grade serous ovarian carcinoma (HGSC), and express serous tubal intraepithelial carcinoma (STICs) precursor lesions.
Purpose of the Study:
- To investigate the role of PAR2 in early ovarian cancer development and progression.
- To evaluate PAR2 as a potential predictive biomarker for ovarian cancer in high-risk individuals.
- To develop and assess a novel therapeutic compound targeting PAR2 signaling.
Main Methods:
- Quantitative analysis of PAR2 expression in fallopian tubes of BRCA carriers versus healthy individuals.
- In vivo studies involving knockdown of Par2 to assess its effect on ovarian cancer peritoneal dissemination.
- Development and testing of a cyclic peptide compound, Pc(4-4), targeting the PAR PH binding motif.
Main Results:
- PAR2 was found to be overexpressed in the fallopian tubes of high-risk BRCA carriers compared to healthy controls.
- Knockdown of Par2 significantly inhibited ovarian cancer peritoneal dissemination in vivo.
- The novel compound Pc(4-4) effectively binds to the PAR PH binding domain, blocking crucial signaling pathways and attenuating PAR2's oncogenic activity, thereby inhibiting ovarian cancer spread in mice.
Conclusions:
- PAR2 overexpression in fallopian tubes may serve as an early predictive marker for ovarian cancer.
- Targeting the PAR PH binding motif with compounds like Pc(4-4) shows therapeutic potential for STICs and ovarian cancer.
- This study highlights the significance of PAR PH binding motif signaling in ovarian cancer and introduces Pc(4-4) as a promising therapeutic agent.
